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Gadolinium‑based contrast agents in neurofibromatosis type 1 (Review)

  • Authors:
    • Florentina Năstase
    • Diana Sabina Radaschin
    • Elena Niculeț
    • Bogdan Ioan Stefanescu
    • Aurel Nechita
    • Draganescu Miruna
    • Liliana Baroiu
    • Arbune Manuela
    • Alin Laurenţiu Tatu
  • View Affiliations

  • Published online on: March 23, 2021     https://doi.org/10.3892/etm.2021.9962
  • Article Number: 530
  • Copyright: © Năstase et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Gadolinium (symbol Gd) is the chemical element with atomic number 64 and is aductile rare‑earth metal, and +3 is its most frequent oxidation state. Gadolinium has an ionic radius of 0.99 Å and is nearly identical to the one of Ca2+. Gd3+ and Ca2+ can become toxic to biological systems if complete. It slowly reacts with atmospheric oxygen to form a black coating and in nature it is usually found only in an oxidized form. Gadolinium usually has impurities similar to those of other rare‑earth metals, when separated, because of their similar chemical properties. Neurofibromatosis type 1 (NF1) or von Recklinghausen's disease is an autosomal dominant disorder of tissues of ectodermal origin, accounting for over 90% of neurofibromatosis cases. Diagnosis is primarily clinical and the central nervous system is commonly involved. The screening of the brain with magnetic resonance (MR) imaging is utilised to evaluate the patients with neurofibromatosis type 1 and as an aid in the diagnosis of asymptomatic patients when clinical criteria are not met.

1. Introduction

Gadolinium (Gd) has the atomic number 64. It is a heavy metal and belongs to the family of lanthanides. The oxidation state of gadolinium that is met often is +3. Gadolinium has an ionic radius of 0.99 Å and is almost identical to the one of Ca2+ (1). Gd3+ and Ca2+ can become toxic to biological systems if it compete. When administered to humans in chelated forms the presence of free gadolinium is avoided, thereby reducing its toxicity (2,3). Gd is capable of inducing a strong magnetic field that influences the degree of relaxivity of the protons of water molecules, resulting in a signal increase in MRI (4-6).

2. Development of gadolinium complexes

Runge first introduced the term of gadolinium-based contrast agent (GBCA) in 1982 at the Radiologic Society of North America meeting in Chicago (7,8). GBCAs were thereafter produced commercially because this increases detection of the lesion. Fig. 1 shows the combined form of Gd-DTPA-Magnevist (also known as gadopentetate dimeglumine). In 1988, this complex was first authorized for use. Subsequently, gadolinium was used in the following complexes: Gd-DOTA-Dotarem (also known as gadoterate meglumine) (Fig. 2), Gd-HP-DO3A-ProHance (gadoteridol) (Fig. 3), and Gd-DTPABMA-Ominiscan (gadodiamide) (Fig. 4) (9). Following identification of the complexes, GBCAs were used for more than 30 years in more than 100,000,000 patients (1).

3. Findings

The administration of gadolinium complexes rarely induces side effects and they can be divided into two groups: i) non-allergic reactions (fatigue, headache, arthralgia, gustatory perversion, flushed feeling, nausea, vomiting) and ii) idiosyncrasic allergy-like reactions (periorbital edema, rash, erythema, respiratory failure, chest pressure) (10,11). The frequency of side effects is similar to medical systemic or topical drugs used for various clinical conditions (12-21). Classified by the severity, the acute reactions to GBCA are: Mild, moderate and severe (10). The mild ones are auto-limited events, show no progress, are the most common and do not require medical treatment, except for skin reactions for which an antihistamine drug can be administered. Skin reactions occur in 0.07 and 2.4% of cases. Moderate reactions require medical treatment such as antihistamines, or transport to emergency room and occur in 0.004-0.7% of cases. The patient life is subjected to immediate risk by severe reaction; however, such reactions do not exceed 0.001-0.01% (10,11). If patients have a history of allergy, hypersensitivity to a gadolinium-based contrast agent or if they receive the contrast agent at a rapid rate, complications may occur (6).

Neurofibromatosis type 1 (NF1) or von Recklinghausen's disease is an autosomal dominant disorder involving tissues of ectodermal origin and represents over 90% of neurofibromatosis cases. Initially, the diagnosis is clinical (22). Symptoms manifest differently in each patient with a highly variable expression, even those within the same family (23,24). The diagnostic criteria take into account the cutaneous, neurological, ocular and skeletal manifestations to which is added the genetic component. These criteria were established in 1988 during the Neurofibromatosis - NIH Consensus Development Conference (22). If two or more criteria out of the seven are present, a clinical diagnosis can be made. The criteria are: i) prepubertal: Six or more than six 'café-au-lait' spots >5 mm and >15 mm, postpubertal; ii) two or more neurofibromas or one or more plexiform neurofibroma; iii) axillary or inguinal freckle (Crowe sign); iv) glioma of the optic nerve; v) two or more than two iris hamartomas; vi) sphenoid wing dysplasia, cortex of long bones thin(with/without pseudarthrosis); vii) a 1st degree relative with neurofibromatosis type 1 diagnosed using the above criteria (25).

The central nervous system is commonly involved in NF1. The screening of the brain with magnetic resonance (MR) imaging is utilised to evaluate the disease progression and as an aid in the diagnosis of asymptomatic patients when clinical criteria are not met (26-29). The most common intracranial abnormalities in NF1 patients are astrocytomas of the optic pathways, as indicated in the MRI of an 8-year-old female patient (Fig. 5). Surfaces with abnormal T-2 signal intensity are observed with high frequency and represent hamartomas or heterotopias as identified in an 8-year-old patient (Fig. 6).

4. Discussion

Progression of these lesions in the second decade of life dictates the need for strict monitoring to exclude neoplasia. In adults the safety of contrast material has been well established, and according to preliminary data that it is also safe for use in children. Contrast administration is recommended when pre-contrast studies show abnormalities, when tumor is suspected, when improved lesion delineation is necessary, and when postoperative evaluation is required to ascertain tumor recurrence (30). Approximately 15% of all patients with NF1 have brain anomaly on MRI (27). The lesions are often multiple (29,30), in characteristic locations: The pons, cerebellar white matter, midbrain, splenium of the corpus callosum and internal capsule. Cerebellar tumors can compress the brain and the fourth ventricle (appearing hydrocephalus) and treatment may require surgical resection. On suspicion of a tumor, administrating contrast material can be helpful to fully delineate and help characterize it, with other investigations being performed for genetic or congenital disorders (30-34).

Rehabilitation of patients can be applied at any stage of disease; consequently, the objectives change as the disease advances. The use of preventive rehabilitation ensures the maintenance of maximum functional independence. A decline in functional skills due to tumor progression leads to rehabilitation playing a supportive role via accommodating patients with anatomic and physiologic limitations. Palliative rehabilitation is recommended for the terminal stages of illness and isused to improve and maintain comfort and quality of life.

5. Conclusions

Contrast administration may be used to maximize tumor detection in basic MR and to determine the stability of neoplasms in follow-up exams. However, if there no new symptoms develop the contrast may not be necessary in patients with, for example, myelin vacuolization. Nevertheless, GBCA is safe and the patients tolerate it well.

Acknowledgements

Not applicable.

Availability of data and materials

The information generated and analyzed during the current study is available from the corresponding author on reasonable request.

Authors' contributions

All authors have had equal participation and equal rights to this article. FN and ALT were major contributors in writing the manuscript. FN, ALT, DM, AM, LB, DSR, BIS, AN and EN contributed to the conception and design of the work, as well as revising the manuscript. DM, BIS, AN and LB helped analyze the data for the work. AM revised it for important intellectual content. ALT and AN approved the final version to be published. All authors agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References

1 

Tomonori K, Hiroshi O, Toyoda K and Kitajima K: Brain gadolinium deposition after administration of gadolinium-based contrast agents. Jpn J Radiol. 34:3–9. 2016.PubMed/NCBI View Article : Google Scholar

2 

Sherry AD, Caravan P and Lenkinski RE: A primer on gadolinium chemistry. J Magn Reson Imaging. 30:1240–1248. 2009.PubMed/NCBI View Article : Google Scholar

3 

Thomsen HS, Morcos SK, Almen T, Almén T, Bellin MF, Bertolotto M, Bongartz G, Clement O, Leander P, Heinz-Peer G, Reimer P, et al: Nephrogenic systemic fibrosis and gadolinium-based contrast media: Updated ESUR Contrast Medium Safety Committee guidelines. Eur Radiol. 23:307–318. 2013.PubMed/NCBI View Article : Google Scholar

4 

Bellin MF: MR contrast agents, the old and the new. Eur J Radiol. 60:314–323. 2006.PubMed/NCBI View Article : Google Scholar

5 

Niendorf HP, Alhassan A and Balzer TH: Safety and risk of gadolinium-DTPA: Extended clinical experience after more than 20 million applications. Magn Monograph. 1–38. 1998.

6 

Granata V, Cascella M, Fusco R, dell'Aprovitola N, Catalano O, Filice S, Schiavone V, Izzo F, Cuomo A, Petrillo A, et al: Immediate adverse reactions to gadolinium-based MR contrast media: A retrospective analysis on 10.608 examinations. Biomed Res Int. 2016(3918292)2016.PubMed/NCBI View Article : Google Scholar

7 

Runge VM, Ai T, Hao D and Hu X: The developmental history of the gadolinium chelates as intravenous contrast media for magnetic resonance. Invest Radiol. 46:807–816. 2011.PubMed/NCBI View Article : Google Scholar

8 

Runge VM, Steward RG, Clanton JA, Jones MM, Lukehart CM, Partain CL and James AE Jr: Work in progress: Potential oral and intravenous paramagnetic NMR contrast agents. Radiology. 147:789–791. 1983.PubMed/NCBI View Article : Google Scholar

9 

Hao D, Ai T, Goerner F, Hu X, Runge VM and Tweedle M: MRI contrast agents: Basic chemistry and safety. J Magn Reson Imaging. 36:1060–1071. 2012.PubMed/NCBI View Article : Google Scholar

10 

The American College of Radiology. Manual on Contrast Media Version. Version 10.3.2018. Accessed from: http://www.acr.org/.

11 

Ersoy H and Rybicki FJ: Biochemical safety profiles of gadolinium-based extracellular contrast agents and nephrogenic systemic fibrosis. J Magn Reson Imaging. 26:1190–1197. 2007.PubMed/NCBI View Article : Google Scholar

12 

Brănișteanu DE, Pintilie A, Dimitriu A, Cerbu A, Ciobanu D, Oanta A and Tatu AL: Clinical, laboratory and therapeutic profile of lichen planus. Medical Surgical J. 121:25–32. 2017.

13 

Tatu AL, Ciobotaru OR, Miulescu M, Buzia OD, Elisei AM, Mardare N, Diaconu C, Robu S and Nwabudike LC: Hydrochlorothiazide: Chemical structure, therapeutic, phototoxic and carcinogenetic effects in dermatology. Rev Chim. 69:2110–2114. 2018.

14 

Fekete GL and Fekete L: Cutaneous leukocytoclastic vasculitis associated with erlotinib treatment: A case report and review of the literature. Exp Ther Med. 17:1128–1131. 2019.PubMed/NCBI View Article : Google Scholar

15 

Ciobotaru OR, Lupu MN, Rebegea L, Ciobotaru OC, Earar K and Miulescu M: Dexamethasone-chemical structure and mechanisms of action in prophylaxis of postoperative side effects. Rev Chim. 70:843–847. 2019.

16 

Tatu AL and Cristea VC: Unilateral blepharitis with fine follicular scaling. J Cutan Med Surg. 21(442)2017.PubMed/NCBI View Article : Google Scholar

17 

Lupu M, Miulescu M, Sandu MN, Filip I, Rebegea L, Ciobotaru O, Stoleriu G, Earar K, Voinecsu CD, Oana R and Ciobotaru OR: Cannabinoids: Chemical structure, mechanisms of action, toxicity and implications in everyday life. Rev Chim. 70(627)2019.

18 

Nwabudike LC, Elisei AM, Buzia OD, Miulescu M and Tatu AL: Statins. A review on structural perspectives, adverse reactions and relations with non-melanoma skin cancer. Rev Chim. 69:2557–2562. 2018.

19 

Ardeleanu V, Dobre M and Georgescu AM: Deep facial wrinkle treatment outcome after first injection of reticulated hyaluronic acid. Rev Chim. 66:2129–2131. 2015.

20 

Nwabudike L and Tatu AL: Response to - chronic exposure to tetracyclines and subsequent diagnosis for non-melanoma skin cancer in a large Mid-Western US population. J Eur Acad Dermatol Venereol. 32(e159)2018.PubMed/NCBI View Article : Google Scholar

21 

Tatu AL, Ionescu MA and Nwabudike LC: Contact allergy to topical mometasone furoate confirmed by rechallenge and patch test. Am J Ther. 25:e497–e498. 2018.PubMed/NCBI View Article : Google Scholar

22 

Neurofibromatosis. Conference statement. National Institutes of Health Consensus Development Conference. Arch Neurol. 45:575–578. 1988.

23 

Antônio JR, Goloni-Bertollo EM and Trídico L: Neurofibromatosis: Chronological history and current issues. An Bras Dermatol. 88:329–343. 2013.PubMed/NCBI View Article : Google Scholar

24 

Tatu AL and Nwabudike LC: The treatment options of male genital lichen sclerosus et atrophicus short title for a running head: Treatments of Genital Lichen Sclerosus Conference: 14th National Congress of Urogynecology (Urogyn)Location: Eforie, Romania Date: SEP 07-09, 2017. Proceedings of the 14th national congress of Urogynecology and the national conference of the Romanian association for the study of pain, pp262-264, 2017.

25 

Nica SC, Mihailescu G, Nica SM, Baetu C, Clatici VG and Buruga I: Neurofibromatosis-one disease for a multidisciplinary team. RoJCED. 3:38–49. 2016.

26 

Lund AM and Skobby F: Optic gliomas in children with neurofibromatosis type 1. Eur J Pediatr. 150:835–838. 1990.PubMed/NCBI View Article : Google Scholar

27 

Elster AD: Radiologic screening in neurocutaneous syndromes: Strategies and controversies. AJNR Am J Neuroradiol. 13:1078–1082. 1992.PubMed/NCBI

28 

Truhan AP and Filipek PA: Magnetic resonance imaging: Its role in the neuroradiologic evaluation of neurofibromatosis, tuberous sclerosis and Sturge-Weber syndrome. Arch Dermatol. 129:219–226. 1993.PubMed/NCBI View Article : Google Scholar

29 

Bognanno JR, Edwards MK, Lee TA, Dunn DW, Roos KL and Klatte EC: Cranial MR imaging in neurofibromatosis. Am J Roentgenol. 151:381–388. 1988.PubMed/NCBI View Article : Google Scholar

30 

Bonawitz C, Castillo M, Chin CT, Mukherji SK and Barkovich AJ: Usefulness of contrast material in MR of patients with Neurofibromatosis type 1. AJNR Am J Neuoradiol. 19:541–546. 1998.PubMed/NCBI

31 

Tatu AL: Umbilicated blue black lesion on the lateral thorax. J Cutan Med Surg. 21(252)2017.PubMed/NCBI View Article : Google Scholar

32 

Ardeleanu V, Frincu LL and Georgescu C: Neoangiogenesis-assessment in esophageal adenocarcinomas. Indian J Surg. 77 (Suppl 3):S971–S976. 2015.PubMed/NCBI View Article : Google Scholar

33 

Ardeleanu V, Chebac GR, Georgescu C, Vesa D, Frâncu L, Frîncu LD and Păduraru D: The modifications suffered by the peri-esophageal anatomical structures in the hiatal hernia disease: A qualitative and quantitative microanatomic study. Rom J Morphol Embryol. 51:765–770. 2010.PubMed/NCBI

34 

Fekete GL and Fekete JE: Steatocystoma multiplex generalizata partial suppurativa-case report. Acta Dermatovenerol Croat. 18:114–119. 2010.PubMed/NCBI

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Spandidos Publications style
Năstase F, Radaschin DS, Niculeț E, Stefanescu BI, Nechita A, Miruna D, Baroiu L, Manuela A and Tatu AL: Gadolinium‑based contrast agents in neurofibromatosis type 1 (Review). Exp Ther Med 21: 530, 2021
APA
Năstase, F., Radaschin, D.S., Niculeț, E., Stefanescu, B.I., Nechita, A., Miruna, D. ... Tatu, A.L. (2021). Gadolinium‑based contrast agents in neurofibromatosis type 1 (Review). Experimental and Therapeutic Medicine, 21, 530. https://doi.org/10.3892/etm.2021.9962
MLA
Năstase, F., Radaschin, D. S., Niculeț, E., Stefanescu, B. I., Nechita, A., Miruna, D., Baroiu, L., Manuela, A., Tatu, A. L."Gadolinium‑based contrast agents in neurofibromatosis type 1 (Review)". Experimental and Therapeutic Medicine 21.5 (2021): 530.
Chicago
Năstase, F., Radaschin, D. S., Niculeț, E., Stefanescu, B. I., Nechita, A., Miruna, D., Baroiu, L., Manuela, A., Tatu, A. L."Gadolinium‑based contrast agents in neurofibromatosis type 1 (Review)". Experimental and Therapeutic Medicine 21, no. 5 (2021): 530. https://doi.org/10.3892/etm.2021.9962